Sex-specific role for 5-HT2A receptor in psychedelic-induced extinction of opioid rewarding properties

Emerging evidence suggests that classical psychedelics may offer therapeutic potential for opioid use disorder (OUD) by alleviating key hallmarks such as altered reward processing and dependence. However, the mechanisms behind these effects remain unclear. Our data demonstrate that a single administration of the psychedelic psilocybin (PSI) reduces conditioned behavior and withdrawal induced by the opioid oxycodone (OXY) in male mice but not in females, and this effect is mediated via the 5-HT2A receptor (5-HT2AR). We show that the sex-specific attenuation of OXY preference is driven by 5-HT2AR activation in frontal cortex pyramidal neurons projecting to the nucleus accumbens (NAc). Additionally, PSI modulates epigenomic regulation following repeated OXY exposure and induces sex-specific NAc dendritic structural plasticity independently of 5-HT2AR. Notably, female frontal cortex and NAc show fewer changes at gene enhancer regions in response to PSI, repeated OXY, or combined PSI-OXY treatment compared to males, with the frontal cortex exhibiting more pronounced sex differences than the NAc at the epigenomic level. Together, these results provide novel insights into the neural and epigenetic mechanisms of psychedelic-induced plasticity in OUD, while also highlighting sex differences in PSI's modulation of reward pathways and its therapeutic potential. MOWChIP-seq (Zhu et al. Nature Protocols 14 (2019) 3366-3394) was performed on neuronal neclei extracted from mouse frontal cortex (FC) and nucleus accumbens (NAc) to investigate impact of psilocybin (PSI) treatment on epigenomic regulation following repeated oxycodone (OXY) administion in make and female mice. Mice received three separate administrations of OXY (3 mg/kg) or vehicle on consecutive days (days 1-3), with 24-hour intervals between doses, followed by a single dose of PSI (1 mg/kg) or vehicle (day 4), resulting in four distinct experimental groups: VEH-VEH, VEH-PSI, OXY-VEH, and OXY-PSI. On day 5, FC and NAc tissue samples were collected for H3K27ac profiling. Neuronal nuclei were extracted and isolated by FACS, followed by MOWChIP-seq on 10,000 nuclei per sample.